Aging in humans is associated with a progressive decline in cognitive function, the consequences of which are enormous for affected individuals. Any scientific advance that could delay or prevent age-related cognitive decline would have a profound impact at every level of society given the demographic changes that are occurring with an exponentially increasing percentage of elderly individuals and the percentage of those individuals who are affected by cognitive decline. The use of animal models has greatly accelerated the pace of research on factors that influence cognitive function and age-related changes. One of the most robust interventions that can enhance cognitive function is physical activity. This has been shown in organisms ranging from rodents to humans. Despite the importance and potency of this intervention, the mechanisms by which exercise enhances cognitive activity remain elusive. Here we propose to test the provocative hypothesis that there are factors secreted by muscle that promote neurogenesis and synaptic plasticity to maintain cognitive function and that these factors are increased by muscle activity during exercise (exercise factors). This hypothesis is firmly rooted in the expanding field of research on muscle as a secretory organ, participating in various endocrine networks that function to regulate physiological phenomena such as energy metabolism, angiogenesis, and bone formation. Within the context of regulation of cognitive function, we propose that a muscle-brain axis is an evolutionarily conserved endocrine pathway that links two primordial organ systems, with muscle-derived factors promoting maintenance of neuronal homeostasis. We will use both in vitro and in vivo approaches to explore this hypothesis in murine models of neurogenesis, neuronal function, and cognitive activity. Capitalizing on our expertise in plasma proteomics, we will characterize the muscle proteome from control muscle and muscle altered by exercise or aging. Both muscle and brain (hippocampus) will be tested for transcriptional and epigenetic changes induced by exercise, both to explore the mechanisms by which exercise modifies muscular and neuronal function and also to test for any molecular memory to explain any persistent effects of exercise on the brain. Direct tests of secretomes will be performed using parabiotic pairings and plasma injections, and candidate testing will include studies of neurogenesis in vitro and muscle-specific gene deletions in vivo. These multifaceted approaches will allow us to characterize the muscle-brain axis, to examine the molecular basis and regulation of that axis with exercise, and to understand the basis for the lasting effects of exercise on neuronal activity, each of which would provide an entirely new framework within which to understand the beneficial effects of physical activity on brain function and together offering a potentially revolutionary approach to the treatment of age-related cognitive decline.